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3D replicon distributions arise from stochastic initiation and domino-like DNA replication progression.

Löb D, Lengert N, Chagin VO, Reinhart M, Casas-Delucchi CS, Cardoso MC, Drossel B - Nat Commun (2016)

Bottom Line: Critical model features are: spontaneous stochastic firing of individual origins in euchromatin and facultative heterochromatin, inhibition of firing at distances below the size of chromatin loops and a domino-like effect by which replication forks induce firing of nearby origins.The model reproduces the empirical temporal and chromatin-related properties of DNA replication in human cells.We advance the one-dimensional DNA replication model to a spatial model by taking into account chromatin folding in the nucleus, and we are able to reproduce the spatial and temporal characteristics of the replication foci distribution throughout S-phase.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Institute for Condensed Matter Physics, Technische Universität Darmstadt, 64289 Darmstadt, Germany.

ABSTRACT
DNA replication dynamics in cells from higher eukaryotes follows very complex but highly efficient mechanisms. However, the principles behind initiation of potential replication origins and emergence of typical patterns of nuclear replication sites remain unclear. Here, we propose a comprehensive model of DNA replication in human cells that is based on stochastic, proximity-induced replication initiation. Critical model features are: spontaneous stochastic firing of individual origins in euchromatin and facultative heterochromatin, inhibition of firing at distances below the size of chromatin loops and a domino-like effect by which replication forks induce firing of nearby origins. The model reproduces the empirical temporal and chromatin-related properties of DNA replication in human cells. We advance the one-dimensional DNA replication model to a spatial model by taking into account chromatin folding in the nucleus, and we are able to reproduce the spatial and temporal characteristics of the replication foci distribution throughout S-phase.

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Induced firing probability.The firing probability of origins that are close to forks follows a Gaussian probability density, indicated as shaded areas next to the forks. Firing at positions closer than di=55 kbp to a fork is inhibited and the probability density is cutoff at values below 0.1. The relative probabilities of individual origins are indicated by dark grey bars. All four forks to the left of the chromosome boundary belong to a single 1D fork cluster (assuming that neighbouring forks are <1 Mbp apart). The chromosome boundary near the right edge of the image isolates chromatin belonging to different chromosomes and thus cuts off the induced firing range of the rightmost fork.
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f1: Induced firing probability.The firing probability of origins that are close to forks follows a Gaussian probability density, indicated as shaded areas next to the forks. Firing at positions closer than di=55 kbp to a fork is inhibited and the probability density is cutoff at values below 0.1. The relative probabilities of individual origins are indicated by dark grey bars. All four forks to the left of the chromosome boundary belong to a single 1D fork cluster (assuming that neighbouring forks are <1 Mbp apart). The chromosome boundary near the right edge of the image isolates chromatin belonging to different chromosomes and thus cuts off the induced firing range of the rightmost fork.

Mentions: Due to the induced firing process, the probability for very short distances between firing origins would be much higher than experimentally observed (Fig. 2b). Thus, we introduced a distance around active forks, where firing of potential origins is inhibited (the inhibition distance—di). A range of the di values from 7 to 120 kbp was selected based on the reported correlation of distances between preferentially activated origins2728293031 and average sizes of the chromatin loops in different functional chromatin organization models1432. To find the most probable value for di we compared the experimental distribution of inter-origin distances (Fig. 2b) with the distribution obtained from simulations varying the di value (5 kbp steps) by calculating the χ2 value as well as the Kullback–Leibler divergence. Both measures have a broad minimum for di values between 35 and 55 kb indicating the most probable range. In the simulations presented here, a value of 55 kb was used, because smaller values lead to an increasing total number of origins fired. Figure 1 shows a schematic of the induced firing process in the model. The range of induced firing is determined by the parameter σ, the s.d. of the Gaussian curve, which is used to set the induced firing probabilities of nearby potential origins. Induced firing probabilities below 0.1 are set to zero to avoid the infinite range of the Gaussian curve. Increasing the value of σ broadens the simulated distribution of inter-origin distances shifting the mean towards higher distances and decreasing σ enhances the peak of the distribution below 200 kb. In the range from 100 to 280 kb for the parameter σ there are only minor changes to the distribution of inter-origin distances, therefore it can not be determined more precisely from the given data.


3D replicon distributions arise from stochastic initiation and domino-like DNA replication progression.

Löb D, Lengert N, Chagin VO, Reinhart M, Casas-Delucchi CS, Cardoso MC, Drossel B - Nat Commun (2016)

Induced firing probability.The firing probability of origins that are close to forks follows a Gaussian probability density, indicated as shaded areas next to the forks. Firing at positions closer than di=55 kbp to a fork is inhibited and the probability density is cutoff at values below 0.1. The relative probabilities of individual origins are indicated by dark grey bars. All four forks to the left of the chromosome boundary belong to a single 1D fork cluster (assuming that neighbouring forks are <1 Mbp apart). The chromosome boundary near the right edge of the image isolates chromatin belonging to different chromosomes and thus cuts off the induced firing range of the rightmost fork.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4829661&req=5

f1: Induced firing probability.The firing probability of origins that are close to forks follows a Gaussian probability density, indicated as shaded areas next to the forks. Firing at positions closer than di=55 kbp to a fork is inhibited and the probability density is cutoff at values below 0.1. The relative probabilities of individual origins are indicated by dark grey bars. All four forks to the left of the chromosome boundary belong to a single 1D fork cluster (assuming that neighbouring forks are <1 Mbp apart). The chromosome boundary near the right edge of the image isolates chromatin belonging to different chromosomes and thus cuts off the induced firing range of the rightmost fork.
Mentions: Due to the induced firing process, the probability for very short distances between firing origins would be much higher than experimentally observed (Fig. 2b). Thus, we introduced a distance around active forks, where firing of potential origins is inhibited (the inhibition distance—di). A range of the di values from 7 to 120 kbp was selected based on the reported correlation of distances between preferentially activated origins2728293031 and average sizes of the chromatin loops in different functional chromatin organization models1432. To find the most probable value for di we compared the experimental distribution of inter-origin distances (Fig. 2b) with the distribution obtained from simulations varying the di value (5 kbp steps) by calculating the χ2 value as well as the Kullback–Leibler divergence. Both measures have a broad minimum for di values between 35 and 55 kb indicating the most probable range. In the simulations presented here, a value of 55 kb was used, because smaller values lead to an increasing total number of origins fired. Figure 1 shows a schematic of the induced firing process in the model. The range of induced firing is determined by the parameter σ, the s.d. of the Gaussian curve, which is used to set the induced firing probabilities of nearby potential origins. Induced firing probabilities below 0.1 are set to zero to avoid the infinite range of the Gaussian curve. Increasing the value of σ broadens the simulated distribution of inter-origin distances shifting the mean towards higher distances and decreasing σ enhances the peak of the distribution below 200 kb. In the range from 100 to 280 kb for the parameter σ there are only minor changes to the distribution of inter-origin distances, therefore it can not be determined more precisely from the given data.

Bottom Line: Critical model features are: spontaneous stochastic firing of individual origins in euchromatin and facultative heterochromatin, inhibition of firing at distances below the size of chromatin loops and a domino-like effect by which replication forks induce firing of nearby origins.The model reproduces the empirical temporal and chromatin-related properties of DNA replication in human cells.We advance the one-dimensional DNA replication model to a spatial model by taking into account chromatin folding in the nucleus, and we are able to reproduce the spatial and temporal characteristics of the replication foci distribution throughout S-phase.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Institute for Condensed Matter Physics, Technische Universität Darmstadt, 64289 Darmstadt, Germany.

ABSTRACT
DNA replication dynamics in cells from higher eukaryotes follows very complex but highly efficient mechanisms. However, the principles behind initiation of potential replication origins and emergence of typical patterns of nuclear replication sites remain unclear. Here, we propose a comprehensive model of DNA replication in human cells that is based on stochastic, proximity-induced replication initiation. Critical model features are: spontaneous stochastic firing of individual origins in euchromatin and facultative heterochromatin, inhibition of firing at distances below the size of chromatin loops and a domino-like effect by which replication forks induce firing of nearby origins. The model reproduces the empirical temporal and chromatin-related properties of DNA replication in human cells. We advance the one-dimensional DNA replication model to a spatial model by taking into account chromatin folding in the nucleus, and we are able to reproduce the spatial and temporal characteristics of the replication foci distribution throughout S-phase.

Show MeSH
Related in: MedlinePlus